Matrix metalloproteinases (MMPs) have been implicated in tumor growth, angiogenesis, invasion, and metastasis. There is extensive preclinical data that inhibition of MMP activity results in a reduction in tumor burden and prolongs the survival of treated animals. Synthetic MMP inhibitors (MMPIs) are currently in Phase III clinical trials in a variety of tumor types, and non-small cell lung cancer (NSCLC) trials in particular have been initiated with several different compounds. The results of the initial studies with the broad spectrum inhibitor marimastat (British Biotech) showed little benefit in advanced pancreatic and gastric cancer, but encouraging results in patients without overt metastases. Studies with the MMPI tanomastat (Bayer Corp.), however, were stopped when preliminary results from an adjuvant small cell lung cancer (SCLC) trial demonstrated that the MMPI was performing worse than placebo. These results raised the realization that very little is known about the role of MMPs in lung cancer development and progression. This proposal is designed to test the hypothesis that MMPs are valid therapeutic targets for lung cancer, and to determine the MMP family members that represent the most appropriate targets for MMPIs in NSC and SC lung cancer. The following specific aims are proposed: 1) Determine the expression profile of MMP transcripts and protein in SCLC and NSCLC samples and associate the expression profile with response to MMPI treatment. 2) Determine if MMPIs inhibit MMP activity in lung cancer patients using an ex vivo MMP activity assay, and 3) Determine the efficacy of MMPIs in chemically-induced and orthotopic preclinical models of lung cancer. The availability of mice that are null for several MMP family members provides the opportunity to examine the role of specific MMP family members in these model systems. These studies represent translational research that will guide the selection and application of selective MMPIs to the treatment of lung cancer.